Drug/Small Molecule:

lofexidine

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Description

Lofexidine is an alpha2-adrenergic receptor agonist. It can be used as a short acting anti-hypertensive, but is mostly used to help relieve symptoms of heroin or opiate withdrawal in opiate dependency. It is approved in the United Kingdom, but is still undergoing clinical trials in the United States.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Lofexidine is an alpha2-adrenergic receptor agonist.

Source: Drug Bank

Pharmacology

Lofexidine is an orally active imidazoline adrenergic alpha-2-receptor agonist; and is believed to have a high affinity for 2A receptor subtypes resulting in less anti-hypertensive activity than clonidine, a non-selective alpha-2-receptor agonist. Hypotension may occur in susceptible subjects, accompanied by a decrease in heart rate. Abrupt discontinuation of lofexidine has been, in some cases, associated with a transient increase in blood pressure to higher than pre-treatment levels. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By fooling the brain into believing that catecholamine levels are higher than they really are, lofexidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure. This central action is responsible for the suppression of opiate withdrawal symptoms.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Lofexidine undergoes extensive metabolism in the liver and excretion is mainly by the kidney.

Source: Drug Bank

Protein Binding

80 to 90%

Source: Drug Bank

Absorption

Lofexidine is extensively absorbed and achieves peak plasma concentration at 3 hours after administration of a single dose. Bioavailability is over 90% following oral administration.

Source: Drug Bank

Half-Life

11 hours

Source: Drug Bank

Toxicity

Lofexidine was tolerated at high dosage in singe dose toxicity studies in animals, the LD 50 being >77 mg/kg. With repeat dosing in mice, rats and dogs symptoms related to the pharmacology of the drug (ataxia, sedation, tremor, unkempt appearance and exhaustion) appeared. Overdosage may cause hypotension, bradycardia and sedation.